Relatively little is known of the metabolism of the aliphatic hydroxylamines that are the primary metabolites of amines in some species. Whole animal studies indicated that only a portion of the administered dose is recovered as identifiable metabolites. The losses in recovery could reflect unknown metabolites or metabolites with long half-lives of elimination. Although these metabolites could constitute a small proportion of the administered dose, they could accumulate with chronic treatment because of their long stay in the body and cause deleterious effects. This project will elucidate pathways of metabolism of the N-hydroxy metabolites of amphetamine and phentermine. The conversion of these hydroxylamines to the nitroso and nitro state as well as their subsequent metabolism will be examined in vitro with liver preparations from rat and rabbit. The metabolism of these compounds differ markedly between these species so that a contrast can be made. The involvement of cytochrome P-450 in these oxidations will be examined with induction and inhibition studies. The relationship between these nitrogen metabolites and other metabolites isolated in vivo will be determined by experiments on single step reactions and by stable isotope product-precursor studies. The formation of the tissue bound substances or highly polar metabolites will be assessed with radiochemical methodology. Compounds will be tentatively identified by mass spectral techniques with ultimate proof based on comparison with authentic compounds.